Phase II trial of olaparib in combination with ceralasertib in patients with recurrent osteosarcoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS11575-TPS11575
Author(s):  
Suzanne J. Forrest ◽  
Michael D. Kinnaman ◽  
J Andrew Livingston ◽  
Kieuhoa Tran Vo ◽  
Priscilla Merriam ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Cell Lines ◽  
Phase Ii ◽  
Objective Response ◽  
Parp Inhibitors ◽  
Clinical Activity ◽  
Osteosarcoma Cell ◽  
In Vitro Susceptibility ◽  
Correlative Studies

TPS11575 Background: Osteosarcoma is the most common primary bone tumor, occurring in children, adolescents, and young adults. In contrast to advances in treatment for most childhood cancers, there have been no significant improvements in osteosarcoma outcomes in the past 40 years. Forty percent of osteosarcoma patients will, at some point, have advanced disease which has a very poor outcome with a 5-year overall survival of approximately 20%. Genomic alterations and signatures associated with sensitivity to treatment with DNA damage response (DDR) inhibitors are observed frequently in osteosarcoma. Many osteosarcomas have a unique mutational signature (signature 3) similar to that seen in BRCA1 deficient cancer and response to PARP inhibitors has been seen in osteosarcoma cell lines. Additionally, ATRX, a protein involved in the alternative lengthening of telomeres (ALT), is often inactivated in osteosarcoma. Defects in the ALT pathway may sensitize tumor cells to ATR inhibitors and osteosarcoma cell lines have been shown to be sensitive to ATR inhibition. In vitro susceptibility of osteosarcoma cell lines to ATR and PARP inhibitors, the presence of mutations in genes involved in DDR and the presence of signature 3 in a subset of osteosarcomas serves as the basis for the development of this trial. Methods: This is an ongoing open label, multicenter, phase II clinical trial to evaluate the clinical activity of PARP inhibitor, olaparib, in combination with ATR inhibitor, ceralasertib, in 2 cohorts of patients aged 12-40 with recurrent osteosarcoma (NCT04417062). Patients with unresectable disease are enrolled into Cohort 1. Patients with resectable disease limited to the lung are enrolled into Cohort 2. Patients in both cohorts receive olaparib 300mg orally twice a day on days 1-28 and ceralasertib 160 mg orally once a day on days 1-7 of a 28-day cycle (adult maximum tolerated dose for the combination). For patients in Cohort 2, study treatment also includes surgical resection of lung metastases at protocol-specified timepoints. Patients can remain on treatment for up to 2 years if they have not progressed. For Cohort 1, the primary objective is to determine whether the combination treatment improves the 4-month event-free rate as compared to a historical benchmark from Children’s Oncology Group (COG) trials using a Simon’s two-stage design. In the first stage, ≥3 of 19 patients must be event-free at 4 months to proceed to stage 2. Enrollment into Cohort 2 continues as long as Cohort 1 enrollment is ongoing. For Cohort 2, the primary endpoint is the submission of paired pre- and post-treatment tumor samples for correlative studies. Secondary endpoints include objective response rate, event-free survival, and overall survival. Integrated correlative studies will assess tumor tissue for biomarkers of treatment response and measure circulating tumor DNA longitudinally. Enrollment began November 24, 2020 and is ongoing. Clinical trial information: NCT04417062.

A phase II trial of LEE011 in combination with everolimus in the treatment of advanced well differentiated neuroendocrine tumors of foregut origin.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. TPS546-TPS546 ◽  
Author(s):  
Nitya Prabhakar Raj ◽  
Virginia Kelly ◽  
Jennifer A. Chan ◽  
A. Dasari ◽  
Marinela Capanu ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Disease Progression ◽  
Neuroendocrine Tumors ◽  
Phase Ii ◽  
Drug Combination ◽  
Objective Response ◽  
Metastatic Breast ◽  
Open Label ◽  
Well Differentiated

TPS546 Background: Changes in the retinoblastoma (Rb) tumor suppressor pathway are believed to contribute to the development of well differentiated neuroendocrine tumors (WDNETs). In the pre-clinical setting, loss or downregulation of proteins that normally inhibit the cyclin dependent kinases Cdk4 and Cdk6 have contributed to NET development. Separately, rigorous investigation of everolimus in WDNETs has demonstrated a survival benefit in this patient (pt) population. Pre-clinical data suggests that the Cdk4/Cdk6 inhibitor LEE011 is synergistically active with everolimus. The aim of this study is to evaluate the efficacy and safety of LEE011 in combination with everolimus in pts with advanced WDNETs of foregut origin (thymic, bronchopulmonary, gastric, duodenal, pancreatic). Methods: This study is a multicenter, non-randomized, open-label phase II clinical trial using a Simon two stage optimal design. Main inclusion criteria include: adult patients with WDNET of foregut origin, low to intermediate grade, unresectable and/or metastatic, disease progression ≤ 12 months prior to enrollment, ECOG 0-1. Between 15 and 43 patients will be enrolled from three sites across the US. LEE011 300mg daily, 3 weeks on and 1 week off, in combination with everolimus 2.5mg daily (final dosing based on phase 1b clinical trial performed in metastatic breast cancer; LEE011X2106) will be administered orally until disease progression, unacceptable toxicity, investigator decision, or pt withdrawal. All enrolled pts will be followed by telephone contact for overall survival until death or consent withdrawal. The primary endpoint, progression free survival, will be assessed based on radiographic review by RECISTv1.1. Main secondary endpoints include establishing the safety of this drug combination in this patient population, objective response rate, clinical benefit rate, and overall survival. Correlative objectives include exploring the effect of this drug combination on biomarkers related to the Rb pathway and/or WDNET pathogenesis. This trial began enrollment in 2/27/2017, with 10 patients enrolled to date. Clinical trial information: NCT03070301.

Interim results from the OPTIMAL trial: A phase II clinical trial of combination nivolumab, ipilimumab, and taxane in patients with untreated metastatic non-small cell lung cancer (NSCLC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21683-e21683
Author(s):  
Jeffrey Melson Clarke ◽  
Xiaofei F. Wang ◽  
Lin Gu ◽  
Marvaretta Miesha Stevenson ◽  
Tom Stinchcombe ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase Ii ◽  
Therapeutic Option ◽  
Objective Response ◽  
Phase Ii Clinical Trial ◽  
Response To Treatment ◽  
Smoking History ◽  
Weekly Paclitaxel ◽  
Clinical Activity ◽  
Treatment Naïve

e21683 Background: Combination chemo-immunotherapy is a well-established frontline therapeutic option for treatment naïve NSCLC. Dual immune checkpoint blockade (ICB) with nivolumab (nivo) and ipilimumab (ipi) has demonstrated improved clinical outcomes compared with chemotherapy alone in this setting. Combination dual ICB with low-dose chemotherapy may have advantages of preventing early disease progression and potentiating immunogenic response to treatment. Methods: We are conducting a single arm phase II clinical trial of nivo 360 mg IV Q3 weeks, ipi 1 mg/kg IV Q6 weeks, and weekly paclitaxel 80 mg/m2 IV on d1 and d8 of a 21 day cycle in ECOG 0-1 patients (pts) with treatment naïve NSCLC. Paclitaxel is stopped after a total of 4-6 cycles. The primary endpoint of the trial is progression free survival (PFS) with secondary endpoints of safety and objective response rate (ORR) by independent radiologic review. Interim results are presented from the first 23 evaluable pts, of a planned sample size of 49. Results: 23 pts were enrolled and evaluable with a mean age 63.8 years, 56.5% ECOG 0, 87% current/previous smoking history, and 70% adenocarcinoma. PDL1 score for < 1%, 1-49%, ³ 50% was seen in 9 (39.1%), 4 (17.4%), and 10 (43.5%) pts, respectively. Median time of follow up was 6.5 months (range 1.4–15.0). Partial response was observed in 14 pts, stable disease was seen in 8 pts, and 1 pt progressed during cycle 1, resulting in an ORR of 61%. Grade 3 or higher toxicity at least possibly attributed to study treatment was seen in 47.8% of 23 AE evaluable patients, of which included 4 cases of secondary adrenal insufficiency. Other toxicity rates were as expected for the respective agents. Conclusions: This is the first trial to evaluate weekly paclitaxel with nivo plus ipi in pts with untreated NSCLC. This regimen has demonstrated highly encouraging clinical activity with a manageable toxicity profile. The study is ongoing and updated results will be presented at the annual meeting. Clinical trial information: NCT03573947.

Phase II multicenter study of talazoparib for somatic BRCA1/2 mutant metastatic breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS1110-TPS1110
Author(s):  
Neelima Vidula ◽  
Erica Blouch ◽  
Nora K. Horick ◽  
Erin Basile ◽  
Senthil Damodaran ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Metastatic Breast ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Patient Reported

TPS1110 Background: PARP inhibitors are approved for the treatment of HER2 negative metastatic breast cancer (MBC) with germline BRCA1/2 mutations, based on phase III studies demonstrating an improvement in progression-free survival (PFS) compared to chemotherapy in this population and better patient reported outcomes (Robson, NEJM, 2017; Litton, NEJM, 2018). However, germline BRCA1/2 mutations account for only 5-10% of breast cancer, limiting the current clinical applicability of PARP inhibitors. Somatic BRCA1/2 mutations are detectable in circulating cell-free DNA (cfDNA) in ̃13.5% of patients with MBC; in pre-clinical models, pathogenic somatic BRCA1/2 mutations have been shown to respond to PARP inhibition (Vidula, CCR, 2020). The purpose of this study is to evaluate the efficacy of talazoparib, a PARP inhibitor, in patients with MBC who have somatic BRCA1/2 mutations detectable in cfDNA, in the absence of a germline BRCA1/2 mutation, which we hypothesize will be effective in this setting. This study may help expand the population of patients with MBC who benefit from PARP inhibitors. Methods: This is an investigator initiated multicenter, single arm, phase II clinical trial studying the efficacy of talazoparib in 30 patients with MBC who have pathogenic somatic BRCA1/2 mutations detected in cfDNA. Patients with MBC who are found to have pathogenic somatic BRCA1/2 mutations detected in cfDNA in the absence of a germline BRCA1/2 mutation are eligible. Patients may have triple negative (with ≥ 1 prior chemotherapy), or hormone receptor positive/HER2 negative breast cancer (with ≥ 1 prior hormone therapy). Patients may have received any number of prior lines of chemotherapy, including a prior platinum (in the absence of progression). They must have adequate organ function and ECOG performance status ≤2, and should not have previously received a PARP inhibitor. Patients are treated with talazoparib 1 mg daily until disease progression or intolerability, with serial imaging using CT chest/abdomen/pelvis and bone scan performed at baseline and every 12 weeks, and cfDNA collection every 4 weeks. Primary endpoint is PFS by RECIST 1.1. Patients are being enrolled in a two-stage design with 80% power to demonstrate that the treatment is associated with “success” (PFS > 12 weeks) in ≥53% patients (4% alpha). Secondary endpoints include objective response rate and safety (NCI CTCAE v 5.0). Exploratory analyses include studying serial changes in cfDNA BRCA1/2 mutant allelic frequency and comparing pre-and post-treatment cfDNA for the emergence of BRCA1/2 reversion and resistance mutations. This study is activated and open at Massachusetts General Hospital, where 2 patients are completing screening. It is also opening soon at 6 other academic centers (NCT03990896). Grant support includes a Pfizer ASPIRE award and 2020 Conquer Cancer Foundation of ASCO – Breast Cancer Research Foundation – Career Development Award. Clinical trial information: NCT03990896 .

A phase I/II study of TQ-B2450, a PD-L1 mAb, plus anlotinib in EGFR+ advanced NSCLC patients failed to prior EGFR TKI therapies.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21062-e21062
Author(s):  
Meiqi Shi ◽  
Li Wang ◽  
Shaorong Yu ◽  
Fei Yan ◽  
Wei Peng ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Phase I ◽  
Phase Ii ◽  
Advanced Nsclc ◽  
Phase 1 ◽  
Objective Response ◽  
Platinum Based Chemotherapy ◽  
Egfr Tki ◽  
Clinical Trial Information

e21062 Background: Platinum-based chemotherapy is the standard therapy for the patients(pts) with EGFR-mutation–positive advanced NSCLC failed to prior EGFR TKI therapies. However, the IMpower150 study subgroup analyses showed Atezolizumab (PD-L1) plus bevacizumab and chemotherapy improved overall survival in EGFR TKI treated NSCLC. This ongoing phase I/II study designed to assess the benefit of the chemo-free combination of TQ-B2450, a humanized PD-L1 mAb, plus anlotinib in EGFR+ advanced NSCLC pts failed to prior EGFR TKI therapies. Methods: Pts with EGFR+ advanced NSCLC who failed to prior EGFR TKI therapies were eligible. Pts with previous received platinum-based chemotherapy were excluded. Anlotinib was given orally at dose of 8mg to 12mg for 2 weeks of a 21-day cycle (days 1-14), with TQ-B2450 given at 1200mg every 3 weeks on day 1. Phase I determined RP2D. In the phase II part, pts were assessed for efficacy and tolerability. The primary endpoint for the phase II part is the progression free survival (PFS). Secondary endpoints were objective response rate (ORR) disease control rate (DCR), overall survival (OS), and safety. Assuming an expected the median PFS of 9 months (5 months in chemotherapy), and a loss to follow-up of 10%, a total of 54 pts were required to have 90% power at a two-tailed alpha of 0.05 at the phase II part. Results: As of 12 Jan 2021, 22 pts were enrolled (9 in phase 1, 14 in phase 2). 18 pts were included in efficacy and safety analysis. The median age was 64.5 years with 61% male. 50% pts harbored EGFR exon19 deletion, 44% pts had exon21 L858R mutation. While 39% pts had T790M mutation who progressed after osimertinib treatment. The dose escalation cohort included 9 pts, no dose limiting toxicity occurred. 13 pts in the phase II part were administered with dose of 12 mg for anolitinib and 1200mg for TQ-B2450. Of the evaluable pts(n = 18), ORR was 11.1%, DCR was 77.8%, median PFS was 8.0 months (95% CI 4.9 to 11.1). Most frequent TRAE included hypertension (27.8%), hand and foot skin reaction (22.2%) and proteinuria (16.7%). Grade 3 TRAE occurred in 16.7% pts(3/18 pts), all were hypertension, and no Grade 4/5 TRAE were observed. Dose delay due to TRAE occurred in 22.2% patients while no one discontinued treatment due to TRAE. Conclusions: The chemo-free combination of TQ-B2450, a PD-L1 mAb, plus anlotinib has shown a promising anti-tumor efficacy with a more favorable safety profile for pts with EGFR+ advanced NSCLC who failed to prior EGFR TKI therapies. Pts will be continuously monitored for safety and efficacy readouts (PFS, DOR and OS). Clinical trial information: ChiCTR1900026273. Clinical trial information: ChiCTR1900026273.

scholarly journals Selective MEK Inhibition with AZD-6244 (selumetinib) in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL): A University of Chicago Phase II Consortium Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3990-3990
Author(s):  
Natalie Galanina ◽  
Sonali M. Smith ◽  
Chuanhong Liao ◽  
Adam M. Petrich ◽  
Bernadette Libao ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cell Lines ◽  
Phase Ii ◽  
Germinal Center ◽  
Research Funding ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Clinical Activity ◽  
Free Survival ◽  
Molecular Features

Abstract Introduction: The biology of DLBCL is complex, with a number of clinicopathologic and molecular features impacting outcome. MCT-1 is an oncogene that promotes lymphomagenesis via enhanced cell survival signaling, increased G1 cyclin/CDK activity and overriding cell cycle checkpoints; its expression is substantially elevated in DLBCL without a clear difference in germinal center versus non-germinal center subtypes. Our preliminary studies showed that 1) 85% of DLBCL samples have strong or increased expression of MCT-1via IHC, 2) MCT-1 knockdown induces apoptosis in cell lines, and 3) mutant MCT-1 protein expression attenuates the malignant phenotype via translational changes. (Dai Ca Res 2009 69(19): p. 7835-43) MCT-1 levels are directly regulated by MEK/ERK signaling, providing a rationale to test MEK pathway inhibition as a therapeutic target in DLBCL. AZD-6244 (ARRY-142886, selumetinib) is a novel second generation oral small molecule MEK inhibitor that induces dose dependent apoptosis in DLBCL cell lines and attenuates tumor growth in xenograft models. (Bhalla Blood 2011 118(4): p. 1052-61) In patients with solid tumors, AZD-6244 75mg twice daily has been established as the recommended phase II dose (RP2D). (Adjei JCO 2008 26(13): p. 2139-46) Methods: Eligible relapsed/refractory (R/R) DLBCL patients received AZD6244 hydrogen sulfate at a dose of 75 mg by mouth twice daily continuously for up to eight 28-day cycles or until disease progression or unacceptable toxicity. The primary objective of the study was overall response rate (ORR) with secondary objectives including safety, progression free survival (PFS), overall survival (OS) and pharmacodynamic (PD) analyses. The statistical design used a Simon two-stage design. Due to excessive early toxicity, the protocol was amended to reduce the dose to 50mg twice daily. Results : Sixteen R/R DLBCL pts (9 male, 7 female) with a median age of 70 years (range, 29-86 yrs), median 3 prior regimens (range, 0-6) were enrolled. Cell-of-origin was not prospectively determined, but only 3/10 pts were CD10 positive and 5/9 were MUM1 positive. The median Lactate Dehydrogenase (LDH) at study entry was 483 (range, 194-1128). Two patients withdrew consent prior to treatment exposure. Of 14 patients receiving at least one dose of selumetinib, two had stable disease and the remainder progressed. The median number of treatment cycles was one (range, 1-5). This was partly due to toxicity causing frequent dose interruptions of AZD-6244. Grade ³3 toxicities were observed in 37.5% (15.2 - 64.6%) and included anemia (44%), thrombocytopenia (25%), diarrhea (31%), transaminitis 44%), fatigue (44%); other infrequent toxicities included AV block, LV dysfunction, anorexia and rash. Median progression-free survival (PFS) in all patients was 34 days [95% CI 14-73 days]. Median overall survival (OS) was 129 days [CI 58-134 days]; all but 3 patients (including one patient lost to follow-up) have expired. Conclusion: Despite excellent preclinical rationale to test selective MEK antagonism as a means of modulating MCT-1 and MEK/ERK in DLBCL, AZD-6244 was not well tolerated and had limited clinical activity. Other MEK/ERK inhibitors with a more favorable toxicity profile and/or use of rational synergistic combination therapy should be considered to further evaluate the role of MEC inhibition in this heavily pretreated patient population. (Patel Cancer 2014 19(4): p. 799-805 (Supported by NCI contract N01-CM-2011-00071C) Disclosures Petrich: Seattle Genetics: Consultancy, Honoraria, Research Funding. Westin:Spectrum: Research Funding. Gordon:Northwestern University: Employment; Dr Leo I. Gordon: Patents & Royalties: Patent for gold nanoparticles pending.

Phase I/II Study of Lenalidomide Combined with DA-EPOCH and Rituximab (DA-EPOCH-R2) in Primary Effusion Lymphoma in Patients with or without HIV

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4096-4096
Author(s):  
Kathryn Lurain ◽  
Ramya Ramaswami ◽  
Anaida Widell ◽  
Irene Ekwede ◽  
Jomy George ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Phase I ◽  
B Cell ◽  
Cell Lines ◽  
Phase Ii ◽  
Primary Effusion Lymphoma ◽  
Kaposi Sarcoma ◽  
Research Support ◽  
Receive Research Support

Primary effusion lymphoma (PEL) is a rare, aggressive B-cell neoplasm with a unique clinical profile that is most frequently associated with HIV infection. It generally presents with malignant effusions but may also present with extracavitary masses. It is caused by the gamma-herpesvirus Kaposi sarcoma herpesvirus (KSHV, also called human herpesvirus-8 [HHV-8]), which is also the etiologic agent of Kaposi sarcoma and the plasmablastic form of multicentric Castleman disease (KSHV-MCD). KSHV is known to cause cytokine related severe inflammation associated with elevated human interleukin (IL)-6 and IL-10. There have been no prospective studies in PEL and there is currently no standard therapy for this disease. The prognosis of PEL is poor compared to other HIV-associated lymphomas. PEL has a median survival of 10-22 months when treated with conventional chemotherapy regimens for non-Hodgkin lymphoma according to the most recent retrospective reports. Lenalidomide, a derivative of thalidomide with immunomodulatory activity, has been shown to have in vitro antitumor effects in PEL cell lines. KSHV itself may cause downregulation of immune surface markers as a way to avoid immune detection. Lenalidomide can reverse this and enhance surface expression of major histocompatibility complex-1 and intercellular adhesion molecule-1 in PEL cell lines. Dose-adjusted infusional etoposide, vincristine, and doxorubicin with cyclophosphamide and prednisone (DA-EPOCH) is an anthracycline-based regimen that allows for personalization of dose-intensity, and prior anecdotal experience indicates it has activity in PEL. In combination with rituximab, an anti-CD20 monoclonal antibody, DA-EPOCH has been shown to be safe and effective for HIV-associated diffuse large B-cell lymphoma and Burkitt lymphoma. PEL is a CD20 negative tumor; however, many patients have concurrent KSHV-MCD for which rituximab is the standard treatment. In addition, rituximab may aid in eradication of the KSHV B-cell reservoir, a source of inflammatory cytokines that drive the natural history of PEL. Patients of any HIV serostatus with both effusion and extracavitary presentations, including those with concurrent KSHV-associated diseases, such as Kaposi sarcoma and KSHV-MCD, are eligible. Patients with ECOG performance status of ≤4 are eligible for enrollment. The phase I portion of the study will evaluate the safety, tolerability, and maximum tolerated dose of lenalidomide combined with DA-EPOCH and rituximab (DA-EPOCH-R2). The phase II component will evaluate the activity and overall survival. Patients will receive 6, 21-day cycles of DA-EPOCH-R2. Lenalidomide, initially at 25 mg, will be given on days 1 to 10. Patients will receive rituximab on day 1 and DA-EPOCH on days 1 to 5. Patients with HIV will be prescribed antiretroviral therapy as this is central to controlling HIV viremia and managing KSHV-associated malignancies. The lenalidomide dose will be de-escalated in a second dose group if 2 of 6 patients in phase 1 experience a dose-limiting toxicity. In the phase II portion of the study, 15 evaluable patients will be enrolled at the maximal tolerated dose of lenalidomide. At 12 months follow-up after the last patient has enrolled, a 1-tailed 0.10 alpha level test would have 80% power to determine if the overall survival curve would demonstrate a 1-year overall survival consistent with 45% or better and ruling out 20% or worse survival. Secondary outcomes include the evaluation of the pharmacokinetics of lenalidomide in blood, effusions, and CSF and the effect of DA-EPOCH-R2on concurrent KS, KSHV-MCD, and the KSHV-associated inflammatory cytokine syndrome. The study will also examine the effect of lenalidomide alone and in combination with rituximab and DA-EPOCH on the KSHV viral load, serum cytokines, lymphocyte subset reconstitution, HIV latency reversal, cellular measures of HIV, and the pharmacokinetics of tenofovir and tenofovir-diphosphate in plasma and peripheral blood mononuclear cells. The study began enrollment in July 2017, and 5 patients have been enrolled on the phase I portion. All 5 patients have completed treatment without dose limiting toxicities. Disclosures Lurain: Celgene: Other: I receive research support from Celgene through a CRADA at the NCI; Merck: Other: I receive drug for a clinical trial from Merck through a CRADA with the NCI. Ramaswami:Celgene: Other: I receive research support from Celgene through a CRADA at the NCI; Merck: Other: I receive drug for a clinical trial from Merck through a CRADA with the NCI. Whitby:Patent: Patents & Royalties: co-inventor on US Patent 10,001,483 entitled "Methods for the treatment of Kaposi's sarcoma or KSHV- induced lymphoma using immunomodulatory compounds, and uses of bio- markers.". Uldrick:Merck: Other: drug for a clinical trial from Merck through a CRADA with the NCI; Roche: Other: commercial research support through a CTA with Fred Hutchinson Cancer Research Center; Celgene: Other: research support from Celgene through a CRADA at the NCI; Patent: Patents & Royalties: co-inventor on US Patent 10,001,483 entitled . Yarchoan:Celgene: Other: I research support from Celgene through a CRADA at the NCI; Merck: Other: I receive drug for a clinical trial from Merck through a CRADA with the NCI; Patent: Patents & Royalties: coinventor on US Patent 10,001,483 entitled ; Patent: Patents & Royalties: coinventor on patents on a peptide vaccine for HIV and on the treatment of Kaposi sarcoma with IL12; Patent: Patents & Royalties: immediate family member is co-inventor on patents related to internal- ization of target receptors, on KSHV viral IL6, and on the use of calreticulin and calreticulin fragments to inhibit angiogenesis.

scholarly journals 388 A trial to evaluate the safety, immunogenicity, and clinical activity of a helper peptide vaccine plus PD-1 blockade (Mel64, PATHVACS: PD-1 antibody and T-helper vaccine and correlative studies)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A421-A421
Author(s):  
Craig Slingluff ◽  
Kimberly Chianese-Bullock ◽  
Ileana Mauldin ◽  
Walter Olson ◽  
Kelly Smith ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Objective Response ◽  
Advanced Melanoma ◽  
Clinical Activity ◽  
Cell Responses ◽  
Pd1 Blockade

BackgroundA multipeptide vaccine containing 6 melanoma-associated peptides to stimulate helper T cells (6MHP) is safe and immunogenic and has clinical activity. A phase I/II trial was designed to evaluate safety and immunogenicity of 6MHP vaccines plus PD1 blockade.MethodsParticipants with measurable advanced melanoma, age ≥ 18 years, and ECOG performance status 0–1 were administered 6MHP vaccine intradermally and subcutaneously in an incomplete Freund’s adjuvant on days (D) 1, 8, 15, 43, 64, and 85. Pembrolizumab 200 mg was administered intravenously every 3 weeks for up to two years. Biopsies of accessible tumors at baseline and D22 were analyzed by multiparameter immunofluorescence histology. Primary endpoints were safety (CTCAE 4.03) and immunogenicity (ex vivo IFNγ ELIspot assay). Secondary and exploratory endpoints included changes in the tumor microenvironment (TME), and clinical outcomes.ResultsTwenty-two eligible participants were enrolled and treated, including 6 naïve to PD-1 Ab and 16 anti-PD-1 Ab-experienced. Median follow-up was 20 months. Treatment-related adverse events (any grade) experienced by >20% were injection site reactions, fatigue, anemia, nausea, fever, bruising, and rash. Treatment-related dose limiting toxicities (grade 3 elevated AST, skin ulcer, or uveitis) were observed in 3 (14%), which did not cross the study safety bound. Objective clinical responses were observed in 23% (1 CR, 4 PR), including 4/6 anti-PD-1 Ab-naive (67%) and one 1/16 anti-PD1 Ab-experienced (6%). Four participants (18%) had SD as best radiographic response (18%), all in the Ab-experienced cohort. T cell responses to 6MHP were detected in seven participants (32%) by week 13 and were associated with clinical response (CR/PR 80% vs. SD/PD 18%; p = 0.01). Overall survival was prolonged for anti-PD-1 Ab naïve vs experienced (p = 0.0048), for those with T cell response (p = 0.045, landmark analysis after week 13), and for those with objective response (p = 0.0148). TME evaluation in 12 participants revealed significant increases by D22 in the densities (per mm2) of CD8+ T cells (p = 0.0186), CD20+ B cells (P = 0.002), and Tbet+ cells (p = 0.034).ConclusionsIn patients with advanced melanoma, combined treatment with the 6MHP vaccine plus pembrolizumab was safe, increased intratumoral T and B cells, as well as Th1 (Tbet+) cells, and induced T cell responses that were associated with objective response and with overall survival. The promising objective response rate and overall survival in patients naive to PD1 blockade supports consideration of a larger study to assess definitive benefit in that clinical setting.AcknowledgementsWe acknowledge the support of Merck for providing pembrolizumab at no charge, and the University of Virginia Cancer Center Support grant P30 CA044579 for support of shared resource facilities.Trial RegistrationThe clinical trial Mel64 (PATHVACS) is registered with Clinicaltrials.gov (NCT02515227).Ethics ApprovalThe clinical trial Mel64 (PATHVACS) was performed with IRB (#18174) and FDA approval (IND #10825) and is registered with Clinicaltrials.gov (NCT02515227). Written informed consent was obtained from each participant prior to participation in the study.

Phase II clinical trial of atezolizumab (A) in advanced non-small cell lung cancer (NSCLC) patients (pts) previously treated with PD1-directed therapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS9105-TPS9105
Author(s):  
Saveri Bhattacharya ◽  
Cindy Yun ◽  
Katja Schulze ◽  
Tullia C. Bruno ◽  
Brenda F Kurland ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase Ii ◽  
Progressive Disease ◽  
Promising Result ◽  
Objective Response ◽  
Phase Ii Clinical Trial ◽  
Clinical Activity ◽  
Variable Response ◽  
Immune Biomarkers ◽  
Previously Treated

TPS9105 Background: While inhibition of the PD1 axis is associated with improved response rates vs cytotoxic therapy in pts with previously treated NSCLC, the majority of pts will not benefit from objective response. Anti-PD1 and PD-L1 antibodies block distinct inhibitory pathways, possibly resulting in different clinical outcomes. While anti-PD1 antibodies block PD1 binding to PD-L1 and PD-L2, they do not affect the inhibitory signal of the PD-L1/B7.1 interaction. This trial is critical to establishing the clinical activity of sequencing PD-L1 inhibition in pts previously treated with PD1 directed and identifying candidate biomarkers of response and resistance to PD1/PD-L1 directed therapies. Methods: In this phase II clinical trial, pts with advanced NSCLC with stable or progressive disease on anti-PD1 therapy (nivolumab or pembrolizumab) will be treated with A1200 mg day 1 of a 21-day cycle until disease progression, unacceptable toxicity or death. The kinetics of response to anti-PD1 therapy can be variable and in some cases characterized by pseudo-progression. In order to account for variable response kinetics to PD1 therapy, pts will be enrolled in 3 parallel cohorts based on best overall response (BOR) to PD1 therapy (stable disease; progressive disease; complete or partial response followed by progressive disease). The primary objective is BOR to A. Secondary endpoints include duration of response, progression free survival, overall survival, and safety. 37 pts will be enrolled per cohort. A Simon 2-stage design will be employed with a stopping rule for futility if 0 of the first 11 evaluable patients within a cohort have a confirmed objective response in Stage 1. A promising result would be if ≥3 responses are seen at the conclusion of stage 2. This design has 80% power to detect a true response rate of 15% in each cohort (null rate 2%; alpha 0.05). Mandatory biopsies at time of enrollment, archival tumor pre-PD1 directed therapy, and optional biopsy at the time of progression on A will be collected for exploratory studies of immune biomarkers of response and resistance. Clinical trial information: NCT03014648.

659 AN SINGLE-ARM OPEN-LABEL PHASE II STUDY OF CAMRELIZUMAB PLUS APATINIB AS SECOND-LINE TREATMENT FOR ADVANCED ESOPHAGEAL SQUAMOUS CELL CARCINOMA

2021 ◽  
Vol 34 (Supplement_1) ◽  
Author(s):  
Feng Wang ◽  
Qingxia Fan ◽  
Junsheng Wang ◽  
Tao Wu ◽  
Yonggui Hong ◽  
...  
Keyword(s):  
Overall Survival ◽  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Phase Ii ◽  
Squamous Cell ◽  
Objective Response ◽  
Phase Iii ◽  
Line Treatment ◽  
Second Line

Abstract   Esophageal squamous cell carcinoma (ESCC) as a common malignancy is prevalent in East Asia and in eastern and southern Africa. Although pembrolizumab, nivolumab and camrelizumab are respectively recommended as second-line treatment for advanced ESCC due to improved overall survival (OS), objective response rate (ORR) was modest. New effective treatments are needed. Hence, the study of camrelizumab plus apatinib (VEGFR2 inhibitor) as second-line treatment for advanced ESCC was performed. Methods This ongoing phase II trial (NCT03736863) in six sites in China enrolled pts aged 18-75 with unresectable locally advanced, locally recurrent, or metastatic ESCC that progressed or were intolerant after first-line chemotherapy, and an ECOG performance status of 0-1. Pts received 200 mg camrelizumab intravenously every 2 weeks and apatinib 250 mg orally once per day in 4-week cycles until disease progression, unacceptable adverse events (AEs) or withdrawal of consent. The primary endpoint was investigator-assessed ORR. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS) and OS. Results At data cutoff (Feb 28, 2021), 52 pts were enrolled, including 42 males and 50 with distant metastases, with the median age of 62 years. In the evaluable population of 39 pts, ORR without confirmation was 43.59% and DCR was 94.87%. The median duration of response was 6.9 months (95% CI 4.57–9.23). The median PFS was 6.8 month (95% CI 2.66–10.94). The 12-month overall survival was 52.2%. A total of 80.8% of pts had treatment-related AEs (TRAEs) with 46.2% of grade ≥ 3 TRAEs. The safety profile of camrelizumab and apatinib was consistent with other anti–PD-1 antibodies and angiogenesis inhibitors. Conclusion This is the first study that evaluates the combination anti–PD-1 antibody and anti-angiogenesis inhibitor as a second-line therapy for advanced ESCC. Camrelizumab plus apatinib showed encouraging clinical efficacy and acceptable safety. Further phase III randomized trials are warranted.

Regomune: A phase II study of regorafenib + avelumab in solid tumors—Results of the biliary tract cancer (BTC) cohort.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4096-4096
Author(s):  
Sophie Cousin ◽  
Carine A. Bellera ◽  
Jean Philippe Guégan ◽  
Thibault Mazard ◽  
Carlos A. Gomez-Roca ◽  
...  
Keyword(s):  
Phase Ii ◽  
Adaptive Design ◽  
Objective Response ◽  
Locally Advanced ◽  
Survival Rates ◽  
Previous Treatment ◽  
Progression Free Survival ◽  
Treatment Interruption ◽  
Clinical Activity ◽  
Open Label

4096 Background: Regorafenib (R) has shown promising efficacy in patients (pts) with BTC refractory to standard chemotherapy. Anti-PD1/PD-L1 antibodies have only limited clinical activity. Synergy between R and anti–PD-1/PD-L1 antibodies has been shown in pre-clinical solid tumor models. Methods: This is a single-arm open-label multicentric phase II trial (Bayesian adaptive design) assessing the efficacy and safety of R (160 mg QD 3weeks/4) + avelumab (A) (10 mg/kg every 2 weeks) combination in BTC pts. The primary endpoint was the objective response rate under treatment, based on central review according to RECIST 1.1. Secondary endpoints included: 1-year progression free survival (PFS), 1-year overall survival (OS), and Safety using NCI-CTCAE v5.0. Correlative studies were planned from pts tumor samples obtained at baseline. Results: Between Nov. 2018 and Nov. 2019, 34 BTC pts were enrolled in 4 centers. Median age was 63 (range 36 – 80). Median follow-up was 9.8 months. Median number of previous treatment lines for metastatic or locally advanced disease was: 2 (range 1 – 4). Twenty-nine (85.3%) pts experienced at least 1 dose modification or treatment interruption of R or A due to an adverse event (AE) related to the treatment. The most common grade 3/4 AEs were : Hypertension (17.6%), Fatigue (14.7%), and maculo-papular rash (11.8%). No death was related to the treatment. Among the 29 pts with at least one imaging tumor assessment, 4 (13.8%) achieved a partial response, and 11 (37.9%) demonstrated stable disease including 10 (34.5%) pts with tumor shrinkage. Fourteen pts (48.3%) had progressive disease. The median PFS and OS were 2.5 months (95%CI 1.9 – 5.5) and 11.9 months (95%CI 6.2 – NA) respectively. Baseline tumor samples were available for 27 pts. High IDO and PD-L1 expression at baseline was associated with better outcome. Conclusions: The R+A combination is associated with significant anti-tumor activity with promising survival rates in this heavily pre-treated population. Full Biomarkers analyses will be presented at the meeting. Clinical trial information: NCT03475953.

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